Department of Experimental Surgery-Cancer Metastasis, Medical Faculty Mannheim, University of Heidelberg, Germany.
Centre for Biomedicine and Medical Technology, Medical Faculty Mannheim, University of Heidelberg, Germany.
Int J Cancer. 2017 Nov 1;141(9):1879-1890. doi: 10.1002/ijc.30854. Epub 2017 Jul 24.
The tumor suppressor P53 is a critical regulator of normal cellular homeostasis whose function is either distorted or lost in several cancer types including colorectal cancer (CRC). A small group of microRNAs have come to be recognized as essential mediators of P53 function. In a genome-wide systematic approach, we explored miRNAs that are substantially altered by P53 loss and found miR-30e to be the most significantly deregulated miRNA in P53-knockout human CRC cells. We identified miR-30e-5p to be a novel direct transcriptional target of P53 with gain and loss of function experiments revealing miR-30e-5p to be a significant regulator of tumor cell migration, invasion and in vivo metastasis mediated in part by integrins alpha-6 and beta-1 as novel targets. MiR-30e-5p also significantly reduced tumor cell proliferation by causing G1/S cell cycle arrest, which was achieved by inducing P21 and P27 expression. Finally, we found miR-30e-5p to be lost in resected CRC tumors as compared to normal colon tissues. Taken together, miR-30e-5p is a novel effector of P53-induced suppression of migration, invasion and metastasis.
抑癌基因 P53 是正常细胞内稳态的关键调节因子，其功能在包括结直肠癌（CRC）在内的几种癌症中发生扭曲或丧失。一小部分 microRNAs 已被认为是 P53 功能的重要介质。在全基因组系统方法中，我们探索了受 P53 缺失显著改变的 microRNAs，并发现 miR-30e 在 P53 敲除的人 CRC 细胞中是最显著失调的 microRNA。我们确定 miR-30e-5p 是 P53 的一个新的直接转录靶标，通过获得和丧失功能实验，发现 miR-30e-5p 是肿瘤细胞迁移、侵袭和体内转移的重要调节因子，部分通过整合素 α6 和 β1 作为新的靶标介导。miR-30e-5p 还通过诱导 P21 和 P27 的表达，导致 G1/S 细胞周期停滞，从而显著抑制肿瘤细胞增殖。最后，我们发现与正常结肠组织相比，miR-30e-5p 在切除的 CRC 肿瘤中丢失。总之，miR-30e-5p 是 P53 诱导的抑制迁移、侵袭和转移的新效应因子。
